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ADAM17 is required for EGF-R-induced intestinal tumors via IL-6 trans-signaling.


ABSTRACT: Colorectal cancer is treated with antibodies blocking epidermal growth factor receptor (EGF-R), but therapeutic success is limited. EGF-R is stimulated by soluble ligands, which are derived from transmembrane precursors by ADAM17-mediated proteolytic cleavage. In mouse intestinal cancer models in the absence of ADAM17, tumorigenesis was almost completely inhibited, and the few remaining tumors were of low-grade dysplasia. RNA sequencing analysis demonstrated down-regulation of STAT3 and Wnt pathway components. Because EGF-R on myeloid cells, but not on intestinal epithelial cells, is required for intestinal cancer and because IL-6 is induced via EGF-R stimulation, we analyzed the role of IL-6 signaling. Tumor formation was equally impaired in IL-6-/- mice and sgp130Fc transgenic mice, in which only trans-signaling via soluble IL-6R is abrogated. ADAM17 is needed for EGF-R-mediated induction of IL-6 synthesis, which via IL-6 trans-signaling induces ?-catenin-dependent tumorigenesis. Our data reveal the possibility of a novel strategy for treatment of colorectal cancer that could circumvent intrinsic and acquired resistance to EGF-R blockade.

SUBMITTER: Schmidt S 

PROVIDER: S-EPMC5881468 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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ADAM17 is required for EGF-R-induced intestinal tumors via IL-6 trans-signaling.

Schmidt Stefanie S   Schumacher Neele N   Schwarz Jeanette J   Tangermann Simone S   Kenner Lukas L   Schlederer Michaela M   Sibilia Maria M   Linder Markus M   Altendorf-Hofmann Annelore A   Knösel Thomas T   Gruber Elisabeth S ES   Oberhuber Georg G   Bolik Julia J   Rehman Ateequr A   Sinha Anupam A   Lokau Juliane J   Arnold Philipp P   Cabron Anne-Sophie AS   Zunke Friederike F   Becker-Pauly Christoph C   Preaudet Adele A   Nguyen Paul P   Huynh Jennifer J   Afshar-Sterle Shoukat S   Chand Ashwini L AL   Westermann Jürgen J   Dempsey Peter J PJ   Garbers Christoph C   Schmidt-Arras Dirk D   Rosenstiel Philip P   Putoczki Tracy T   Ernst Matthias M   Rose-John Stefan S  

The Journal of experimental medicine 20180222 4


Colorectal cancer is treated with antibodies blocking epidermal growth factor receptor (EGF-R), but therapeutic success is limited. EGF-R is stimulated by soluble ligands, which are derived from transmembrane precursors by ADAM17-mediated proteolytic cleavage. In mouse intestinal cancer models in the absence of ADAM17, tumorigenesis was almost completely inhibited, and the few remaining tumors were of low-grade dysplasia. RNA sequencing analysis demonstrated down-regulation of STAT3 and Wnt path  ...[more]

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